Suppression of Insulin Production and Secretion by a Decretin Hormone

Alfa, Ronald W.; Park, Sangbin; Skelly, Kathleen-Rose; Poffenberger, Gregory; Jain, Nikhil; Gu, Xueying; Kockel, Lutz; Wang, Jing; Liu, Yinghua; Powers, Alvin C.; Kim, Seung K.

doi:10.1016/j.cmet.2015.01.006

Cited by 120 publications

(150 citation statements)

References 67 publications

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“…However, Akh mutant flies are obese and hypoglycemic but lack a pre-adult metabolic phenotype (Gáliková et al, 2015), which suggests some caution is advisable concerning the functional specificity of cell ablation or global manipulation of neurosecretory cells. In line with this, APC cells were reported to also express and secrete Limostatin, which represses Ilp in IPCs (Alfa et al, 2015), illustrating the close interaction between APC and IPC cells in Drosophila metabolic control.…”

Section: Neurosecretory Cellsmentioning

confidence: 73%

Drosophilaas a model to study obesity and metabolic disease

Musselman

Kühnlein

2018

Journal of Experimental Biology

175

130

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Excess adipose fat accumulation, or obesity, is a growing problem worldwide in terms of both the rate of incidence and the severity of obesity-associated metabolic disease. Adipose tissue evolved in animals as a specialized dynamic lipid storage depot: adipose cells synthesize fat (a process called lipogenesis) when energy is plentiful and mobilize stored fat (a process called lipolysis) when energy is needed. When a disruption of lipid homeostasis favors increased fat synthesis and storage with little turnover owing to genetic predisposition, overnutrition or sedentary living, complications such as diabetes and cardiovascular disease are more likely to arise. The vinegar fly Drosophila melanogaster (Diptera: Drosophilidae) is used as a model to better understand the mechanisms governing fat metabolism and distribution. Flies offer a wealth of paradigms with which to study the regulation and physiological effects of fat accumulation. Obese flies accumulate triacylglycerols in the fat body, an organ similar to mammalian adipose tissue, which specializes in lipid storage and catabolism. Discoveries in Drosophila have ranged from endocrine hormones that control obesity to subcellular mechanisms that regulate lipogenesis and lipolysis, many of which are evolutionarily conserved. Furthermore, obese flies exhibit pathophysiological complications, including hyperglycemia, reduced longevity and cardiovascular functionsimilar to those observed in obese humans. Here, we review some of the salient features of the fly that enable researchers to study the contributions of feeding, absorption, distribution and the metabolism of lipids to systemic physiology.

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Section: Neurosecretory Cellsmentioning

confidence: 73%

Drosophilaas a model to study obesity and metabolic disease

Musselman

Kühnlein

2018

Journal of Experimental Biology

175

130

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“…UAS-AMPKRNAi line (TRiP #25931, Bloomington Stock Center) produced similar phenotypes to UAS-AMPKRNAi (v106200) and was used for most experiments. The UAS-CG9918RNAi line (TRiP #27539, Bloomington Stock Center) has been described 48 . Gr36C -Gal4, Myo1A ts -Gal4, voila -Gal4, and S106 -Gal4 have been described 49–51 (FlyBase).…”

Section: Methodsmentioning

confidence: 99%

An obligatory role for neurotensin in high-fat-diet-induced obesity

Song

Zaytseva

et al. 2016

Nature

219

237

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Obesity and its associated comorbidities (e.g., diabetes mellitus and hepatic steatosis) contribute to approximately 2.5 million deaths annually1 and are among the most prevalent and challenging conditions confronting the medical profession2,3. Neurotensin (NT), a 13-amino acid peptide predominantly localized in specialized enteroendocrine (EE) cells of the small bowel4 and released by fat ingestion5, facilitates fatty acid (FA) translocation in rat intestine6, and stimulates growth of various cancers7; the effects of NT are mediated through three known NT receptors (NTR1, 2 and 3)8. Increased fasting plasma levels of pro-NT (a stable NT precursor fragment produced in equimolar amounts relative to NT) are associated with increased risk of diabetes, cardiovascular disease and mortality9; however, a role for NT as a causative factor in these diseases is unknown. Here, we show that NT-deficient mice demonstrate significantly reduced intestinal fat absorption and are protected from obesity, hepatic steatosis and insulin resistance associated with high fat consumption. We further demonstrate that NT attenuates the activation of AMP-activated protein kinase (AMPK) and stimulates FA absorption in mice and in cultured intestinal cells, and that this occurs through a mechanism involving NTR1 and NTR3/sortilin. Consistent with the findings in mice, expression of NT in Drosophila midgut EE cells results in increased lipid accumulation in the midgut, fat body, and oenocytes (specialized hepatocyte-like cells) and decreased AMPK activation. Remarkably, in humans, we show that both obese and insulin-resistant subjects have elevated plasma concentrations of pro-NT, and in longitudinal studies among non-obese subjects, high levels of pro-NT denote a doubling of the risk of developing obesity later in life. Our findings directly link NT with increased fat absorption and obesity and suggest that NT may provide a prognostic marker of future obesity and a potential target for prevention and treatment.

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“…The human counterpart is supposed to be the peptide neuromedin U, which may inhibit insulin secretion (10). However, more studies are required to support this mechanism, which might be relevant for the metabolic effects of gastric bypass operations.…”

Section: The Incretin Effectmentioning

confidence: 99%

“…The sight, smell, taste, and sensory impulses generated by food presentation, mastication, and swallowing of an appetizing meal undoubtedly result in excitatory signals to the gastrointestinal tract (10). This has been studied in detail in relation to gastric acid secretion, where sham feeding (intake and chewing of an appetizing meal that is prevented from entering the stomach, typically by spitting it out) elicits ;65% of maximal gastric acid secretion (11).…”

Section: Anticipatory Eventsmentioning

confidence: 99%

Roles of the Gut in Glucose Homeostasis

et al. 2016

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The gastrointestinal tract plays a major role in the regulation of postprandial glucose profiles. Gastric emptying is a highly regulated process, which normally ensures a limited and fairly constant delivery of nutrients and glucose to the proximal gut. The subsequent digestion and absorption of nutrients are associated with the release of a set of hormones that feeds back to regulate subsequent gastric emptying and regulates the release of insulin, resulting in downregulation of hepatic glucose production and deposition of glucose in insulin-sensitive tissues. These remarkable mechanisms normally keep postprandial glucose excursions low, regardless of the load of glucose ingested. When the regulation of emptying is perturbed (e.g., pyloroplasty, gastric sleeve or gastric bypass operation), postprandial glycemia may reach high levels, sometimes followed by profound hypoglycemia. This article discusses the underlying mechanisms.

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Suppression of Insulin Production and Secretion by a Decretin Hormone

Cited by 120 publications

References 67 publications

Drosophilaas a model to study obesity and metabolic disease

Drosophilaas a model to study obesity and metabolic disease

An obligatory role for neurotensin in high-fat-diet-induced obesity

Roles of the Gut in Glucose Homeostasis

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